Role of senescence in multiple myeloma tumorigenesis

衰老在多发性骨髓瘤肿瘤发生中的作用

• 批准号: 10571047
• 负责人: Thomas Levin Geiser Andersen
• 金额: $ 40.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571047
• 关键词: Ablation; Acute; Age; Aging; Area; Automobile Driving; Benign; Benign Monoclonal Gammopathies; Biopsy; Bone Marrow; Cell Aging; Cells; Cellular Stress; Characteristics; Chromosome abnormality; Clinical Trials; Clonal Evolution; DNA; DNA Transposable Elements; Data; Data Set; Development; Diagnosis; Disease Progression; Evaluation; Exhibits; Gene Deletion; Gene Expression; Gene Mutation; Genes; Genetic; Genomic Instability; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Hybrids; In Vitro; Incidence; Inflammation; Inflammatory; Interferons; Lead; Malignant Neoplasms; Mediating; Methylation; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; Nucleic Acids; Obesity; Oncogene Activation; Oncogenes; Oncogenic; Pathology; Patients; Pharmacology; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Precancerous Conditions; RNA; Risk Factors; Role; Stains; Techniques; Testing; Translating; United States; aged; bone; cell transformation; in vivo; mouse model; neoplastic cell; premalignant; prevent; promoter; response; senescence; success; therapeutic development; tool; tumor; tumorigenesis; tumorigenic

Abstract Multiple myeloma (MM) is an incurable, plasma cell (PC) malignancy that progresses from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although MGUS and SMM PCs exhibit similar oncogenic mutations to MM PCs, they are considered benign and it is unclear what drives tumorigenesis of these pre-malignant PCs. Aging is the primary risk factor for cancers, including MM; it is therefore unsurprising that aging and tumorigenesis exhibit shared mechanisms. One of these shared mechanisms is cellular senescence. Cellular senescence is induced in response to cellular stress, such as oncogenic mutations, and activates growth arrest to prevent tumor formation. However, the accumulation of senescent cells with age contributes to aging pathologies, including cancer. Although deletion or inhibition of genes necessary for senescence induction leads to tumor formation, elimination of senescent cells reduces tumor incidence in aged mice. This suggests that senescent cell accumulation may create a pro- tumorigenic microenvironment; alternatively, pre-tumor cells may themselves be senescent and targeted by senescent cell elimination strategies. In support of this, we found that both MGUS and SMM PCs have enrichment of cellular senescence genes. In addition, SMM PCs show characteristics of late-senescence, including an interferon senescence-associated secretory phenotype (SASP) and the accumulation of cytosolic ssDNA and DNA:RNA hybrids that are associated with increased genomic instability. These findings support a role for PC senescence in monoclonal gammopathies, and suggest a potential mechanism that may ultimately drive tumorigenesis. Importantly, clonal PCs have also been shown to induce senescence in the bone marrow microenvironment (BMME), suggesting additional mechanisms by which senescence may promote a permissive niche for MM tumorigenesis. Thus, we hypothesize that senescence within PCs and their proximate BMME drives progression of MGUS/SMM to MM. In this application, we propose to use genetic mouse models and human patient-derived cells and bone biopsies to ascertain the mechanisms by which senescence drives tumorigenesis through both direct effects on pre-tumor cells and on the BMME. The results of these studies will define a role for senescence, a common aging mechanism, in tumorigenesis. We anticipate that these findings can be rapidly translated to clinical trials targeting the progression of monoclonal gammopathies to MM.

摘要 多发性骨髓瘤（MM）是一种无法治愈的浆细胞（PC）恶性肿瘤， 条件单克隆丙种球蛋白病的意义不明（MGUS）和郁积型多发性骨髓瘤 （SMM）。虽然MGUS和SMM PC表现出与MM PC相似的致癌突变，但它们被认为是 良性的，目前还不清楚是什么驱动这些癌前PC的肿瘤发生。衰老是主要的风险因素 对于癌症，包括MM;因此，衰老和肿瘤发生表现出共同的机制并不奇怪。 这些共同的机制之一是细胞衰老。细胞衰老是由细胞内 应激，例如致癌突变，并激活生长停滞以防止肿瘤形成。但 衰老细胞随年龄的积累导致衰老病理学，包括癌症。虽然删除 或抑制衰老诱导所必需的基因导致肿瘤形成，消除衰老的细胞， 细胞降低老年小鼠的肿瘤发病率。这表明，衰老细胞的积累可能会产生一个亲- 或者，肿瘤前细胞本身可能是衰老的，并被肿瘤微环境所靶向。 衰老细胞消除策略。为了支持这一点，我们发现MGUS和SMM PC都有 细胞衰老基因的富集。此外，SMM PC显示出晚衰老的特征， 包括干扰素衰老相关分泌表型（SASP）和细胞质中 ssDNA和DNA：RNA杂交体与增加的基因组不稳定性相关。这些结果支持 PC衰老在单克隆丙种球蛋白病中的作用，并提出了一种潜在的机制， 驱动肿瘤发生。重要的是，克隆PC也被证明可以诱导骨髓衰老 微环境（BMME），这表明衰老可能促进一个允许的 MM肿瘤发生的小生境。因此，我们假设PC及其邻近BMME内的衰老 驱动MGUS/SMM向MM的进展。在该应用中，我们提出使用遗传小鼠模型， 人类患者来源的细胞和骨活检，以确定衰老驱动的机制 通过对前肿瘤细胞和BMME的直接作用来抑制肿瘤发生。这些研究的结果将 定义衰老在肿瘤发生中的作用，这是一种常见的衰老机制。我们预计这些发现 可以迅速转化为针对单克隆丙种球蛋白病进展为MM的临床试验。